Derivatives of polycyclic gamma-pyrones

ABSTRACT

The present invention relates to novel polycyclic gamma-pyrone derivatives having a hydroxymethyl group on the 3-position, and to a novel process for their production. These compounds, and pharmaceutical compositions containing these compounds, are useful for the treatment of allergic conditions and for the treatment of hyperacidity.

United States Patent von Strandtm ann et al.

[ 1 Apr. 22, 1975 DERIVATIVES OF POLYCYCLIC GAMMA-PYRONES Inventors: Maximilian von Strandtmann,

Rockaway; John Shavel. .lr.. Mendham; Sylvester Klutchko, Hackettstown; Marvin P. Cohen.

New Milford. all of NJ'.

Assigneez- Warner-Lambert Company, Morris Plains. NJ.

Filed: Aug. 13, 1973 Appl. No.: 387,861

Related U.S. Application Data Continuation-impart of Scr. No. 309,329 Nov. 24, 1972. Pat. No. 3.798.240, which is a continuation-in-part of Ser. No. ll2.765. Feb. 4. 197 l, abandoned.

u.s. Cl 260/3452; 424/283 Int. Cl com 7/32 Field of Search 260/3452 Primary Examiner-John Ford Attorney. Agent, or Firm-Albert H. Graddis; Frank S. Chow; Anne M. Kelly [57] ABSTRACT The present invention relates to novel polycyclic gamma-pyrone derivatives having a hydroxymethyl group on the 3-position. and to a novel process for their production. These compounds, and pharmaceutical compositions containing these c'ompounds. are useful for the treatment of allergic conditions and for the treatment of hyperacidity.

6 Claims. N0 Drawings DERIVATIVES OF POLYCYCLIC GAMMA-PYRONES SUMMARY OF THE INVENTION This invention related to novel 3-(hydroxymethyl) derivatives of polycyclic gamma-pyrones having the formula I:

and to a novel process of their preparation, starting with the corresponding o-hydroxy-w-(methylsulfinyl- )acetonaphthone. These novel compounds, and novel pharmaceutical compositions containing these compounds, are useful for the treatment of allergic conditions and for the treatment of hyperacidity.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of this invention having the general formula 1:

wherein the Z ring has one of the following structures:

are active orally or by injection in preventing the allergic and asthmatic reactions in mammals such as cats, dogs, guinea pigs and the like. Thus, for example, in tests conducted according to the procedures described in Life Sciences, 7, 465 (1963), and in Proc. Soc. Exptl. Biol. Med., 81,584 (1952), the compounds of this invention when administered to the respective animals such as rats and guinea pigs at a dose of about 5 to mg/kg are capable of alleviating allergic and asthmatic conditions in these animals.

The compounds of this invention are useful in providing symptomatic relief of allergic conditions such as asthma, hay fever and the like. Generally speaking, these compounds are administered orally, by injection or in the form of an inhaler at a dose of about 5 to 100 mg/kg.

The compounds of formula 1 also exhibit antisec re; tory effects and are therefore useful in relieving gastric hyperacidity.

At a dosage of 20 mg/kg, administered intraperitoneally, the subject compositions are effective in reducing gastric acidity in the pylorus ligated rat when tested according to the procedure of H. Shay, Gastroenterology, 5, 43, (1945).

For parenteral administration, the pharmaceutical compositions containing the compounds of formula I may be administered as aqueous suspensions for intramuscular injection. These are prepared, for example, by suspending the active ingredient in sterile water.

The compounds of formula I may also be formulated with known pharmaceutical d iluents such as water, lactose, powdered sugar, mannitol and the like into dosage forms such as tablets, capsules, and the like.

Certain derivatives of the 3-(hydroxymethyl)polycyclic gammapyrones of formula I also display antiallergenic and acid inhibiting properties. Thus, the corresponding 3-formyl-gamma-pyrones, which are obtained by oxidizing compounds of formula 1 of this invention, are useful in the treatment of allergic c'ondi According to the present invention, novel compounds of the formula I are obtained by reacting the starting material III below: v

O '0 CH S CH C 2 3 III wherein Z ring is as defined above, with two moles of formaldehyde, under basic conditions, to obtain intermediate II below:

CH OH wherein the Z ring is as defined above. A solvent solution ofintermediate ll is then heated to eliminate methylsulfenic acid (CH SOH) and obtain the desired compoundshaving formula 1. The compounds of formula 1 may be obtained from o-hydroxy-w-(methylsulfinyl- )acetonaphtones with or without isolation of the intermediate compounds ll, according to the novel process of this invention.

The starting materials 111 are prepared by the reaction of the corresponding ortho-hydroxy carboxylic acid esters (5,6,7,S-tetrahydro-3-hydroxy-2- naphthoate and ,6,7,8-tetrahydrol -hydroxy-2- naphthoate) with sodium mcthylsulfinyl carbanion gencrated by the action of sodium hydride on dimethyl sulfoxide. Starting materials 111 and the process for preparation are more fully described in co-pending application Ser. No. 392,152, filed Aug. 27, 1973 which is, in

turn, a continuation-in-part of our co-pending application Ser. No. 174,947, filed August 25, 1971, and now US. Patent 3,801,644.

In order to further illustrate the practice of the invention the following examples are included:

EXAMPLE I H CH OH 6,7,8,9-tetrahydro-3-(hydroxymethyl)-4H-naphtho[2,3,-b]pyran-4-one.

To a solution of 40 g of K CO in water is added g of 5',6',7',8'-tetrahydro-3'-hydroxy-2-(methylsulfinyl)-2'-acetonaphthone with stirring. A clear solution is obtained by the addition of 15 ml of methanol. The solution is treated with 34 ml of formalin, and after 15 min. an oil separates out. The mixture is extracted three times with 100 ml portions of CHCl Combined extracts are dried over Na SO and concentrated to an oil under reduced pressure. The oil is dissolved in 125 ml of toluene and the solution in boiled for 1/2 hr. On cooling, crystals form. These are filtered off and recrystallized from absolute ethanol; mp l29.5l3 l .5C.; yield 6 g (43%).

Anal. Calcd for C H O C, 73.02; H, 6.13. Found: C, 73.25; H, 6.23.

EXAMPLE ll cu, 0H

methanol and 27 m1 of formalin is added to the solu- 65 acetonaphthone. The mixture is treated with 40 ml of 1 wherein the Z ring has one of the following structures:

2. A compound according to claim which is 6,7,89- tetrahydro-3-(hydroxymethyl)-4H-naphtho[2,3- blpyran-4-one.

3. A compound according to claim 1 which is 7,8,9,1- 0-tetrahydro-3-( hydroxymethyl )-4H-naphtho[ 1,2- blpyran-4-one.

40 4. A compound of the formula 11:

n on 0.. 4s 2 cuii 1 wherein the Z ring has one of the following structures:

S. A compound according to claim 4 which is 2,3,6,7-

,8,9-hexahydro-3-(hydroxymethyl)-3-(methylsulfiny1)- 4H-naphtho[2,3-b]pyran-4-one.

6. A compound according to claim 4 which is 2,3,7,8- ,9,10-hexahydro-3-(hydroxymethyl)-3- (methylsulfinyl)-4l-lnaphtho['1,2-b-pyran-4one. 

1. A COMPOUND OF THE FORMULA 1:
 1. A compound of the formula I:
 2. A compound according to claim 1 which is 6,7,8,9-tetrahydro-3-(hydroxymethyl)-4H-naphtho(2,3-b)pyran-4-one.
 3. A compound according to claim 1 which is 7,8,9,10-tetrahydro-3-(hydroxymethyl)-4H-naphtho(1,2-b)pyran-4-one.
 4. A compound of the formula II:
 5. A compound according to claim 4 which is 2,3,6,7,8,9-hexahydro-3-(hydroxymethyl)-3-(methylsulfinyl)-4H-naphtho(2,3 -b)pyran-4-one. 